Heart failure remains the leading cause of death around the globe. Numerous factors contribute to the onset and rise of heart failure, but the increasing prevalence of diabetes and genetic disorders are important contributors. We have identified a novel mutation in the adiponectin receptor 1 (AR1) gene in patients with hypertrophic cardiomyopathy and diabetes. Particularly, the screened patients were negative for mutations in 31 other different sarcomeric and metabolic genes known to be associated with hypertrophic cardiomyopathy metabolic syndrome. Sequencing of the AR1 gene identified a G>A transition at 146th position that replaced the amino acid valine (GUA) into methionine (AUG) (V146M). Pilot data demonstrate that the mutation altered cardiomyocyte contractility, increased cardiac hypertrophy, myocardial fibrosis and compromised in vivo cardiac function, and impaired cardiac insulin responsiveness. The goal of this proposal is to further dissect the direct patho-functional impact of this human mutation on cardiac structure and function, molecular pathogenesis and signaling mechanisms. Using adenoviral gene transfer strategies and transgenic mice with cardiac-specific overexpression of the human AR1V146M and human engineered cardiac tissue, this proposal will test the hypotheses that: a) AR1V146M mutation interferes with adiponectin biological action; b) AR1V146M mutation contributes to impairment of cardiac function and increases vulnerability to the onset of hypertrophic cardiomyopathy and heart failure particularly in the presence of modifying factors or second hits such as diabetes; c) AR1V146M mutation impairs myocardial energy substrates and abrogates adiponectin-mediated cardioprotection. Mapping the disease phenotype and signaling pathway induced by AR1V146M mutation may reveal novel pharmacological targets for prevention of hypertrophic and diabetic cardiomyopathies.